Structural and mechanistic insights into the constitutive Themis–Grb2 complex in T cell signalling
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Abstract
Abstract Positive selection of thymocytes is essential for laying the foundations of the mammalian immune system that include the T cell repertoire, self-tolerance, and prevention of autoimmunity. Themis, the archetypal member of a metazoan protein family featuring distinctive CABIT domains, crucially regulates thymocyte positive selection by linking signalling by the T cell receptor (TCR) to the linker of activation of TCR (LAT). Intriguingly, Themis has been proposed to function via a constitutive complex with the multifunctional adaptor Grb2. Although poised to represent a paradigm shift in our understanding of TCR signalling, the structural and mechanistic basis of such an assembly has remained enigmatic. Here, we present the cryo-EM structure of Themis in complex with Grb2, which reveals how the tandem CABIT domains of Themis engulf the C-terminal SH3 domain of Grb2 (Grb2 SH3C ) to enable its latching onto the proline rich sequence of Themis. The remaining two domains of Grb2 adopt at least three conformational poses set to interact with other binding partners such as Sos1. Structural insights from unbound Themis unmask the pronounced flexibility of the CABIT domains of Themis, which becomes ordered upon binding to Grb2 to create a binding hotspot for their constitutive complex. Indeed, Themis variants that abrogate interactions with Grb2 also fail to activate the tyrosine phosphatase SHP-1 after TCR stimulation, analogous to the functional phenotype of Themis-deficient cells. Collectively, our study draws the blueprint of the Themis-Grb2 complex as a dynamic structural hub in T cell development.
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- Authors
- Clancy, D. M., Sanz-Sanjuan, A., Gilis, E., Tougaard, P., Velghe, I., Van Droogenbroeck, Y., Felix, J., Bloch, Y., Cuadrado, Á. F., Merceron, R., Schenck, S., Vandenabeele, P., Brunner, J. D., Taghon, T., Elewaut, D., & Savvides, S. N.
- Affiliations
- Ghent University (BE)
- Ghent University Hospital (BE)
- University of Copenhagen (DK)
- Deutsches Elektronen-Synchrotron DESY (DE)
- Vrije Universiteit Brussel (BE)
- Corresponding author
- Clancy, Danielle M.
- Savvides, Savvas N.
- ORCID
- Venue
- Nature Communications
- Published
- 2026-05-20
- Volume
- 17
- Issue
- 1
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC13381594
- OpenAlex
- W7161848002
- Cited by
- 0
- References
- 69
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek (G049820N, 1219923N)
- Vlaams Instituut voor Biotechnologie (C0101)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- THEMIS, Grb2, T cell receptor signaling, thymic selection, SH3 domain binding, protein-protein interaction, interdomain flexibility, adaptor protein complexes, T cell signaling
- MeSH terms
- Protein Domains, Animals, Humans, Protein Binding, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, src Homology Domains, Cryoelectron Microscopy, Intercellular Signaling Peptides and Proteins, Mice, GRB2 Adaptor Protein, Protein Tyrosine Phosphatase, Non-Receptor Type 6
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